This is a proposal to establish a Cystic Fibrosis (CF) Research and Translational Core Center at the University of California, San Francisco and collaborating institutions. The focus of the Core Center is to facilitate the discovery and evaluation of novel small-molecule therapies for CF. This proposal is the culmination of 5 years of work establishing a unique academic drug discovery program to identify and characterize inhibitors of CFTR and activators of CF-causing CFTR mutants. The proposed Core Center will fund 7 Cores that will support the activities of 2 Pilot Projects and at least a dozen ongoing CF-related projects. The Core directors and users are in most cases senior CF investigators with recognized expertise in their areas of investigation and a history of productive collaboration. The Cores include: high-throughput screening, clinical resources, cell models, animal models, organic/medicinal chemistry, CFTR biochemistry, and electrophysiology. The principal projects to utilize the Core include the discovery and evaluation of small-molecules: to activate CF-causing CFTR mutants such as deltaF508 and G551D (for treatment of the underlying defect in CF); to inhibit CFTR (for development of CF animal models), to enhance non-viral gene delivery (for CF gene therapy), to kill bacteria (for CF antimicrobial therapy), and to reduce airway surface fluid viscosity (for therapy of CF lung disease). The goal of the research to be enhanced by the Core Center is to develop new small-molecules therapies for CF that can be translated into the clinic.